Structural maturation and folding of secretory and transmembrane proteins begins in the endoplasmic reticulum (ER). These processes are catalyzed by an ER-resident protein-folding machinery comprising molecular chaperones, oxidoreductases, and other protein-modifying enzymes. If demand on the secretory pathway exceeds capacity, these ER-resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms. During such instances of 'ER stress,' affected cells are at increased risk for degeneration and death. Accruing evidence implicates endoplasmic reticulum (ER) stress in the etiology and pathogenesis of diabetes mellitus (both types 1 and 2) in humans. The unfolded protein response (UPR), a collection of signaling pathways that attempt to correct ER stress, has been defined and extensively studied. Under ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. However, irremediable levels of ER stress cause these adaptive measures to end, and instead usher in a terminal UPR that drives cells toward dysfunctional and diseased states, often leading to programmed cell death. We have identified the master UPR regulator-IRE1-as a key gatekeeper of the terminal UPR. IRE1 is a bifunctional kinase/endoribonuclease (RNase) that has divergent outputs that determine cell fate. The overall goal of this project is to advance novel kinase inhibitors for early-stage pharmacological validation of this key target controlling entry of cells into the terminal UPR, and to thereby develop pre-therapeutic lead compounds for disease modification in human diabetes mellitus.